Effects of γ- and Hydroxypropyl-γ-cyclodextrins on the Transport of Doxorubicin across an in Vitro Model of Blood-Brain Barrier

Abstract

Association between doxorubicin (DOX) and ␥-cyclodextrin (␥-CD) or hydroxypropyl-␥-CD (HP-␥-CD) has been examined to increase the delivery of this antitumoral agent to the brain. The stoichiometry and the stability constant of ␥-CD or HP-␥-CD and DOX complexes were determined in physiological medium by UV-visible spectroscopy. By using an in vitro model of the blood-brain barrier (BBB), endothelial permeability and toxicity toward the brain capillary endothelial cells of DOX, ␥-CD, and HP-␥-CD were performed. For each CD, endothelial permeability was relatively low and a disruption of the BBB occurred at 20 M, 20 mM, and 50 mM DOX, ␥-CD, and HP-␥-CD, respectively. Increasing amounts of CDs were added to a fixed DOX concentration. Addition of ␥-CD or HP-␥-CD, up to 15 and 35 mM, respectively, decreased the DOX delivery, probably due to the low complex penetration across the BBB and the decrease in free DOX concentration. Higher CD concentrations increased the DOX delivery to the brain, but this effect is due to a loss of BBB integrity. In contrast to what was observed on Caco-2 cell model with various drugs, CDs are not able to increase the delivery of DOX across our in vitro model of BBB.

DMEM (Dulbecco’s Modified Eagle’s Medium)

“…This phenomenon shows clearly that the inclusion complex does not improve the DOX transport and so that only the free DOX is available. A similar behaviour has been observed with the association of flutamide (used in prostate cancer chemotherapy) and HP-β-CD using the Caco-2 in vitro model (Zuo et al, 2000). The permeability coefficient for this drug across a Caco-2 cell monolayer increased when HP-β-CD concentrations were reduced indicating that the passage was due to freely available flutamide.…”

“…Indeed, as shown on our in vitro BBB model, γ-CD is able to extract cholesterol (13% compared to control) and phospholipids (20% compared to control) from BCEC membranes (Monnaert et al, 2004). Furthermore, a marked reduced toxicity for HP-γ-CD in comparison with γ-CD has already been described towards P388 murine leukaemia cells (Leroy-Lechat et al, 1994).…”

“…Consequently, DOX delivery to the brain is still a challenge for numerous research groups. Indeed, to circumvent the limited access of DOX into the brain, different approaches have been investigated including drug delivery systems such as liposomes (Saito et al, 2004) or nanoparticles (Gulyaev et al, 1999), peptide-vector strategy using DOX linked to cationic peptides (Rousselle et al, 2001), P-gp modulator (Fenart et al, 1998) or osmotic pressure modification (Neuwelt et al, 1981). A bradykinin analogue, RMP-7, can also increase the tight junction permeability of the endothelial cells and enhance delivery of therapeutic agents across the BBB (Bartus et al, 1996).…”

Cyclodextrins as Emerging Therapeutic Tools in the Treatment of Cholesterol-Associated Vascular and Neurodegenerative Diseases

“…For example, it was described on primary bovine brain capillary endothelial cell monolayers mimicking the BBB in vivo that hydroxypropyl-γ-CD and γ-CD increased the permeability of the lipophilic antitumoral drug doxorubicin (DOX) by inhibiting the P-glycoprotein-induced DOX efflux [45,46]. The same effect was reported before in Caco-2 cells, a human in vitro intestinal barrier model, with dimethyl-β-CD delivering an immunosuppressive compound [47].…”

Effective combination treatment of lung cancer cells by single vehicular delivery of siRNA and different kinds of anticancer drugs

“…Various HP-CDs and their derivatives have been reported to form inclusion complexes with such antitumor agents. [38][39][40] The three drugs, respectively, formed inclusion complexes with three HP-CD-(l-Arg) 2 ligands in phosphatebuffered saline (PBS) solution under ultrasonic agitation for 4 hours. UV-visible spectroscopy was carried out to confirm whether such HP-CD-(l-Arg) 2 ligands were able to encapsulate the abovementioned drugs to determine the stability constants of the inclusion complexes and to select the most suitable HP-CD-(l-Arg) 2 for each drug.…”